Derivatives of 1,7,7-trimethyl-2-norbornane-2&#39;-spiro-1&#39;,3&#39;-dioxolane

ABSTRACT

COMPOUNDS OF THE FORMULA   4-(R1-N(-R2)-CH2-),1&#39;&#39;,7&#39;&#39;,7&#39;&#39;-TRI(CH3-)SPIRO(1,3-DIOXOLANE-   2,2&#39;&#39;-NORBORNANE)   IN WHICH R1 AND R2 ARE ALKYLS HAVING 2 OR 3 CARBON ATOMS, OR   R1-N(-R2)-   IS PYRROLIDINO, PIPERDINO, MORPHOLINO OR HEXAMETHYLENEIMINO ARE PREPARED BY REACTING CAMPHOR WITH EPIBROMOHYDRIN TO FORM 4&#39;&#39;-BROMOMETHYL-1,7,7-TRIMETHYL-2-NORBORNANE-2&#39;&#39;SPIRO-1&#39;&#39;, 3&#39;&#39;-DIOXOLANE, WHICH IS THEN REACTED WITH   R1-NH-R2   THE COMPOUNDS POSSESS HYPOTENSIVE, VASODILATORY, SPASMOLYTIC, DIURETIC, ANALGESIC, ANTI-INFLAMMATORY AND ANTIDEPRESSIVE PROPERTIES.

United States Patent 3,816,415 DERIVATIVES 0F 1,7,7 TRIMETI-IYL 2 NOR- BORNANE-2'-SPIRO-1',3'-DIOXOLANE Claude P.-Fauran, Paris, Jeannine A. Eberle, Chat on, Guy M. Raynaud, Paris, and Bernard ,M. Poumas, Meudon-la-Foret, France, assignors to Delalande S.A., Courbevoie (Hauts-de-Seine), France Claims priority, applicatign lrance, Mar. 18, 1971,

US. Cl. 260-247.7 E 7 Claims ABSTRACT OF THE DISCLOSURE Compounds of the formula H2 HaC in which R and R are alkyls having 2 or 3 carbon atoms, or

is pyrrolidino, piperidino, morpholino or hexamethyleneimino are prepared by reacting camphor with epibromohydrin to. form 4'-bromomethyl-1,7,7-trin1ethy1-2-norbornane-2'- spiro-1',3'-dioxolane, which is then reacted with /R1 H-N\ The compounds possess hypotensive, vasodilatory,

spasmolytic, diuretic, analgesic, anti-inflammatory and antidepressive properties.

The present invention relates to novel derivatives of 1,7,7-trimethyl-2-norbornane-2-spiro 1',3 dioxolane, their process of preparation and their therapeutic application.

45 160 ml. of C01 are mixed in a 500 ml. reaction vessel The novel derivatives according to the invention correspond to the general formula:

represents:

a dialkylamino group in which the alkyl radicals comprise two or three carbon atoms, or

a heterocyclic radical selected from pyrrolidino, piperidino, morpholino and hexamethyleneimino.

3,816,415 Patented June I1, 1974 The process according to the invention consists in condensing, in a first stage, camphor of formula: I

. with epibromohydrin of formula:

1 CH,--0H0H,Br

0 (III) in the presence of SnCl in carbon tetrachloride, and then condensing, in a second stage, the 4'-bromomethyl-1,7,7- trimethyl-Z-norbornane-Z'-spiro-1',4'-dioxolane obtained of formula:

0 than... \I/

separated by distillation, with an amine of formula:

in which the group Preparation of 4'-bromomethyl-1,7,7-trimethyl-2-norbornane-2'-spiro-1,3'-dioxolane (Code No. 70155) 0.2 mole of camphor, 0.26 mole of epibromohydrin and provided with agitation means, a thermometer, a CaCl cover and ampoule introduction means. The mixture is heated to 30 C. and a solution of 8 g. of SnCl, in 20 ml. of CCl is added thereto over a period of 1 hour. The mixture is hydrolysed with a solution of 12 g. of soda in 60 ml. of water. The mixture is left for 3 hours, with agitation. Thereafter, the organic phase is decanted, washed with water until it is just neutral, dried over sodium sulfate, evaporated and recovered by distillation of the product obtained.

Boiling point: 123 C. under 2 mm. Hg.

2ND STAGE Preparation of 4' -pyrrolidinomethyl- 1,7,7-trimethyl-2-norb0rnane-2' -spir0-1',3f-di0X01ane (Code No. 70214) 0.3 mole of the bromo compound obtained from the first stage, 1.5 mole of pyrrolidine and 300 ml. of dry benzene are introduced into a l-litre reaction vessel fitted with a refrigerated reflux, agitation means and a CaCl cover. The reaction mixture is maintained under benzene reflux for 10 hours. The mixture is'then cooled, treated with 0.3 mole of 2 N soda, decanted, extracted with ether, dried, evaporated and the product formed is distilled.

' Boiling point=148 C. under 1 mm. Hg.

Yield=89%.

Empirical formula=C H NO Elementary analysis-Calculated '(percent): C, 73.07;

H, 10.46. Found (percent)::,C, 72.52; H, 10.24.

3RD STAGE 0.25 mole of compound No. 70214 prepared in the second stage is dissolved in acetone and the solution obtained is treated with 0.25 mole of maleic acid in acetonic solution with cooling. The solvent is evaporated and the residue is recrystallized from an ethyl acetate-isopropyl ether (60/40) mixture and the resultant product is dried.

Melting point=113 C.

Yield=83%.

Empirical formula=C H NO Elementary analysis.-Calcu1ated (percent): C, 63.77; H, 8.61; N, 3.54. Found (percent): C, 63.81; H, 8.45; N, 3.73.

of a guinea pig when said compounds are added in the perfusion liquid of said organ.

The results obtained with three of the compounds are given in the following Table III.

70 229 2.5 gJmL/mn. 30

(3) SPASMOLYTIC PROPERTIES The compounds of formula (I), introduced into the The c mp n s ste in the following Table I have conserving medium, are capable of opposing the contracbeen prepared by the same methods of operation.

tural action of barium chloride on the isolated duodenum TABLE I R1 Ele enta anal s's N M l i t M lti C m ry y I o ecpo 11 e n alculated Found C d Empirical ular C./mm. point Yield, No. R: Form formula weight Hg 0. percent 0 H' N C H N 70213 Baseu nNOa 5- 1 143/0. 3 59 69. 11 9. 90 68. 76 9. 75 -N O {Maleatm Cz1HaaN01 411.48 133 78 61.29 8.08 61.50 7.85 3. 61

70217 {Base- CnHnNOa 307.46 170/03 74 74. 22 10. 82 74. 68 10.72

N Maleate- CzaHarNOa 423. 53 117 86 65.22 8.81 3.31 65.43 8.89 3. 48

7021s 01H; Base-.. n aiNOa 281.43 133/08 61 72.55 11.10 72.42 10.76 N iMaleate- CZIHHNOG 397. 50 70 63. 45 8. 88 3. 53 63. 29 8. 93 3. 69

CzHs

70229 Ni Maleate- CZZHNNOI -51 130 85 6L52 8.62 3.42 64. 66 8.77 3.60

70295 CaH7 {Basam n as oa 309.48 135/05 7.5 N Maleate. CzaHanNOo 425. 55 69 64. 91 9. 24 3'. 29 64. 98 Y 9. 37 3. 15

CaH-

The compounds of formula (I) have been studied on animals in the laboratory and have been shown to possess hypotensive, vasodilatatory, spasmolytic, diuretic, analgesic, anti-inflammatory and antidepressive properties.

(1) HYPO'TENSIVE PROPERTIES Administered by intravenous means on the anaesthetized rat, the compounds of formula (I) provoke a lowering of the arterial pressure.

The results obtained with a certain number of the compounds are given in the following Table 11:

TABLE II Lowering of arterial pressure Code Dose ad- Percent- No. ministered age Duration 70 213---- 1 mgJkgJIV 45 60 mn. 70 217.--. 2 mg./kg./IV 20 run. 70 218-... 1mg.Ikg./IV 60 30 mm. 70 229..-. 1 mgJkgJIV 30 mm. 70 295..-- 1 mgJkgJIV 25 30 mm.

(2) VASODI-LATATORY PROPERTIES The compounds of formula (I) are capable of augmenting the 110w 0f the coronary vessels of the isolated heart of the rat. This activity is evaluated by taking papaverine as standard.

By way of example, the spasmolytic activity of compound Nos. 70214, 70217 and 70229 is equivalent to that of papaverine, whilst that of compound No. 70218 is equal to half that of papaverine.

(4) DI'UR ETIO PROPERTIES (5) ANALGESIC PROPERTIES The compounds of formula (I), administered by oral means on the mouse, are capable of reducing the number of painful stretchings prdoduced by the intraperitoneal injection of acetic acid. 7

The results obtained with a certain number of compounds are given in the following Table 'IV:

TABLE IV Percentage diminution of number of painful stretohings Code No. of compound tested Dose administered (6) ANTI-INFLAM'MATORY PROPERTIES These properties are shown by a reduction of the underplanatary oedema provoked by the local injection of a phlogogenic agents, such as carraghenin, to a rat following oral administration thereto the compounds of formula (I).

By Way of example, a reduction of 45% of the underplanatary oedema is obtained by administration of 200 mg./kg./PO of compound No. 70213 or 50 mg./kg./PO of compound No. 70214 or 70229.

(7) ANTIDEPRESSI'VE PROPERTIES TABLE V Toxicity to the mouse Code No. of compound Dose Percentage tested administered mortality 2,000 mg./kg./PO 1,200 m ./k ./PO 250 750 mgikg. PO .250 850 mg./kg./PO =50 750 mg./kg./PO 50 70 295 1,000 mg./kg./PO :50

The compounds of formula (I) are useful in the treatment of hypertensions, circulatory insufiiciencies, odemas, painful infiammations and others and in that of depressions.

They may be administered by oral means in the form of tablets, drages, and gelules containing 50 to 200 mg. of active ingredient (3 to times a day), by parenteral means in the form of ampoules containing 10 to 100 mg. of active ingredient (1 to 2 times a day) and by rectal means in the form of suppositories containing 25 to 150 mg. of active ingredient (1 to 2 times a day).

Accordingly, the present invention also relates to a therapeutic composition comprising a compound of the general formula (I) together with a therapeutically acceptable carrier.

6 What we claim is: 1. A compound of the formula i /o\ OHCH; H20 l /R1 l 0- HCHzN\ H10 H30 I CH3 H: R;

in which R and R are alkyls having 2 or 3 carbon atoms, or

is pyrrolidino, piperidino, morpholino or hexamethyleneimino and the pharmacologically acceptable acid addition salts thereof.

2. A compound as claimed in claim 1, in which R and R are ethyl.

3. A compound as claimed in claim 1, in which R and R are propyl.

4. A compound as claimed in claim 1, in which is pyrrolidino.

5. A compound as claimed in claim 1, in which is piperidino.

6. A compound as claimed in claim 1, in which is morpholino.

7. A compound as claimed in claim 1, in which is hexamethyleneimino.

References Cited UNITED STATES PATENTS 3,641,039 2/1972 Rakoczi et al. 260-292 3,654,357 4/1972 Bretschneider et al. 260552 R 3,707,558 12/1972 Bretschneider et al.

OTHER REFERENCES Chem. Abstracts, 64:9552a (1966).

HENRY R. JILES, Primary Examiner G. T. TODD, Assistant Examiner US. Cl. X.R.

UNITED STATES (PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3 816 415 Dated June 1974 Claude P. Fauran, Jeannine A. Eberle, Guy M. Raynaud lnventofls) and Bernard M. Pourrias s It is certified that error appears in the aboveidentified patent: and that said Letters Patent are hereby corrected as shown below: 7

Col. 6, line 5; correct the formula to read as follows:

CH3 Y I C O CH2 I O CH CH N /C\ H2O H3C CH3 Signed and sealed this 1st day of October 1974.

(SEAL) Attest:

McCOY M. GIBSON JR. C. MARSHALL ZDANN Attesting Officer Commissioner of Patents USCOMM-DC 60376-P69 fl U. 5. GOVERNMENT PRINTING OFFICE 1 "ID 0366-334.

- FORM Po-1050 (10-69) 

